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Biotech / Medical : ARIAD Pharmaceuticals -- Ignore unavailable to you. Want to Upgrade?

To: John Dwyer who wrote (205)	12/11/1997 5:45:00 AM
From: Jongmans	Respond to of 4474

see on this thread input 198 Martin

To: John Dwyer who wrote (205)	12/11/1997 9:17:00 AM
From: r. peter Dale	Respond to of 4474

Thanks John - well worth checking out. Wonder if a similar approach could express tyrosine hydroxylase/dopa decarboxylase to directly replace dopamine in the striatum. Also CholAc transferase in the hipp of AD patients. Good stuff. These reports not only reinforce the principle of the methodology but clearly indicate the specificity of its clinical application. The matter of temporal regulation is less clear. Best wishes, Peter

To: John Dwyer who wrote (205)	12/11/1997 1:48:00 PM
From: Dulane U. Ponder	Respond to of 4474

As always, John, you add great substantive content to this thread. Thanks.

To: John Dwyer who wrote (205)	12/11/1997 8:40:00 PM
From: r. peter Dale	Read Replies (1) \| Respond to of 4474

John - The article is interesting and the claims are valid to the degree they support the efficacy of the delivery system. The overall success of the 'principle' suggests Ariad's approach can work in vivo. My problem with the study is that is a flawed/incomplete design: there is only one vector delivery time point presented - three weeks prior to striatal 6-OHDA injection (e.g. the Parkinson-like lesion). In a more 'lifelike' scenario - where the lesion already exists or is progressing - the results may be dramatically different. Having high levels of growth factor present prior to 'disease' onset is of questionable value. A 'who cares?' to this criticism would not be inappropriate. I'll discount any Parkinson's relevance and read this as a significant methodology paper. Peter

To: John Dwyer who wrote (205)	12/15/1997 10:32:00 PM
From: r. peter Dale	Read Replies (1) \| Respond to of 4474

The timing of Ariad's recent price swoon seems particularly interesting since Gilman et al. (i.e. Ariad) have published 2 papers in the last 3 months: The 1st (PNAS 94, 10618, Sept. 1997) directly addresses the feasibility of the dimerization system Ariad will apply to targeted drug delivery. The paper reports on the development of a 'new' compound, AP1510, which can act as a substitute substrate for the FK506 binding protein (FKBP). AP1510 induced elevated dimerization (over FK506 and others) as measured by targeted Fas-FKBP induced apoptosis or transcriptional activation. AP1510 is smaller than FK506 and thus can enter cells more readily - and can activate FKBP-fused constructs several hundred fold. AP1510 also worked in stably transfected cells, a paradigm where other dimerizers were ineffective. THM: AP1510 was shown to produce both homo- and heterodimers, it could do this in the cytoplasm as well as the nucleus, and it could work effectively at low levels of protein where other dimerizers failed. Ariad has successfully designed and tested a potent dimerizer. A paper in the 11 Dec. issue of J. Clin. Invest., using generally similar constructs, showed that an orally administered compound (rapamycin) could exert precise transcriptional control of implanted, stably transfected cells. Some questions remain of the discordant absorption/clearance kinetics; however, the degree of dose (rapamycin) response (gene transcription) concordance was striking. And lots was learned about tolerance, cell dosage, etc. Ariad has successfully tested an orally regulated gene therapy system. Is anyone aware of other biotechs or labs as far along with similar directed drug delivery systems? Has anyone else read these papers? This is good stuff! John Dwyer - I'd appreciate your comments. Peter [Thx to mz for the flag]